This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and validate clinically relevant, quantifiable biomarkers of diagnostic and therapeutic responses for blood, vascular, cardiac, and respiratory tract dysfunction. Acquired lymphatic vascular dysfunction (lymphedema) is a common, chronic, debilitating disease that is frequently under-recognized or misdiagnosed, and many patients never receive treatment. The inability to accurately predict high- risk individuals is a source of fear and frustration among patients. Previous work in a murine model of this disease has shown remarkable histological similarity to human acquired lymphedema. Utilizing genome-wide transcriptional profiling of lymphedema mouse skin, we have identified a relatively restricted list of genes and biological pathways. By analogy, genome- wide transcriptional profiling of human cutaneous, disease-specific expression patterns should lead to focused cellular and molecular insights. Paired microarray of diseased and normal tissue in the same individual will be used to identify candidate serological biomarkers. Human skin will be obtained through punch biopsy of diseased and normal limbs in individuals with unilateral acquired lymphedema;sera will be banked for subsequent assay. Paired analysis will identify significantly upregulated, target genes that encode easily measured secreted proteins with plausible relationship to lymphedema-relevant biological pathways. A multi-marker serological assay for these proteins will be developed and prospectively validated in cohorts of disease-positive and -negative subjects. This study is proposed to lead to the methodical development of a multi-marker serological bioassay with a high degree of utility and specificity for acquired lymphedema. An important investigational and clinical instrument will result, with its capacity to facilitate diagnosis, risk stratification, and monitoring of therapeutic responsiveness in patients with acquired lymphatic vascular insufficiency. Acquired lymphedema causes chronic swelling of the limb(s) that is frequently under-recognized or misdiagnosed: treatment delays are common, and many patients never receive treatment. The current investigation is designed to undertake a targeted molecular approach that will predictably lead to the development of accurate, non-invasive, serum-based testing for lymphedema. The availability of this clinical tool should predictably enhance both diagnosis and treatment. PUBLIC HEALTH RELEVANCE: Acquired lymphedema causes chronic swelling of the limb(s) that is frequently under-recognized or misdiagnosed: treatment delays are common, and many patients never receive treatment. The current investigation is designed to undertake a targeted molecular approach that will predictably lead to the development of accurate, non-invasive, serum-based testing for lymphedema. The availability of this clinical tool should predictably enhance both diagnosis and treatment.